JP2021073209A - Ophthalmic compositions of rifamycins and uses thereof - Google Patents

Abstract

To provide ophthalmic pharmaceutical formulations comprising a rifamycin compound.SOLUTION: Provided are ophthalmic pharmaceutical compositions or formulations comprising one or more rifamycin compounds selected from the group consisting of rifampicin, rifabutin, rifapentine. In one aspect, the invention relates to methods of treating an ocular disease, disorder or condition comprising administering to a patient in need thereof an ophthalmic composition comprising an effective amount of a rifamycin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin.SELECTED DRAWING: None

Description

Reference to Related Applications This application is a US provisional patent application No. 62 / 027,189 filed on July 21, 2014, a specification of No. 62 / 136,222 filed on March 20, 2015, and Claiming priority over the specification of the same No. 62 / 174,884 of the application of June 12, 2015, the respective contents of the application are incorporated herein by reference in their entirety.

As used herein, a pharmaceutically acceptable composition or a composition suitable for topical administration to the eye, which comprises a therapeutically effective amount of an antibacterial agent, wherein the antibacterial agent comprises a rifamycin derivative in a preferred embodiment. , Compositions, methods of their preparation, and methods of their use in the treatment of various disorders are provided.

Loss of vision includes aging, macular degeneration, ocular histoplasma syndrome, myopia, diabetic retinopathy,
And all of these, such as inflammatory diseases, are common problems associated with various diseases of the eye resulting from angiogenesis in the cornea, retina, or choroid.

Age-related macular degeneration (AMD) usually affects the elderly and is the center of vision due to retinal damage (AMD)
It is a common eye disease that results in the loss of vision of the macula of the retina. Some peripheral vision remains, but it is difficult or impossible to read or recognize the face. There are two main types of macular degeneration: atrophic (dry) and exudative (wet). Dry (non-exudative)
In the mold, cell debris called drusen accumulates between the retina and the choroid. In the more severe moist (exudative) form, blood vessels grow from the choroid behind the retina. AMD is a major cause of blindness in populations over the age of 65 and is caused by the abnormal development of blood vessels behind the retina.
Due to the aging population, the advanced AMD population will increase by 11% to 3.3 million. Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is associated with AMD choroidal neovascularization (CN)
It has become the standard standard for the treatment of V). Full-length anti-VEG as a treatment option for wet AMD
Bevacizumab (Avastin, Genentech (San Franc), which is an F antibody
isco, CA), an affinity maturation fragment, ranibizumab (Lucentis, Genen)
tech), Pegaptanib Sodium (Macugen, OSI / Eyetech In)
c. ), And Aflibercept (Eilea, Regeneron, Tarrytown)
n, NY), as well as other anti-VEGF agents. However, intravitreal injection is
It is a process that requires high accuracy because it is performed using a needle under local anesthesia. In this process, the needle must be inserted into the vitreous humor that fills the cavity between the lens and the retina, and great care must be taken not to damage the retina. Therefore, an easy treatment of AMD is highly desirable. Therefore, there are requirements for additional treatments as well as routes of administration and methods for the treatment of eye disorders such as AMD.

The present invention generally relates to pharmaceutical compositions or formulations suitable for administration into the eye. In some aspects, the invention relates to an ophthalmic pharmaceutical composition or formulation comprising one or more rifamycin compounds selected from the group consisting of rifampicin, rifabutin, rifapentine.

In one aspect, the invention comprises administering to a patient in need thereof an ophthalmic composition comprising an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin. Concerning how to treat an eye disease, disorder, or condition. In some aspects, the invention relates to methods of treating disorders mediated by inhibition of angiogenesis in retinal tissue. In another aspect, the invention relates to a method of treating age-related macular degeneration using an ophthalmic composition of a riffamycin compound. In yet another aspect, the invention relates to a method of protecting retinal ganglion cells and / or protecting them from brain injury using an ophthalmic composition of a riffamycin compound. In a further aspect, the invention comprises an ophthalmic composition comprising an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin or a pharmaceutically acceptable salt thereof.
It relates to a method of reducing the thickness of the retina in a patient who needs it, including administration to the patient.

In one aspect, as used herein, up to about 1% (g / composition 100 mL (weight / volume) or (
w / v)), or about 0.1% to about 1%, or about 0.25% to about 1%, or about 0.5
% To about 1%, or about 0.1% to about 0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0.5% retina and at least 1. Eye angiogenesis in the retina of a patient in need thereof, comprising topically administering a pharmaceutically acceptable composition containing one pharmaceutically acceptable additive to the eye of the patient, including the retina. A method of inhibiting the disease is provided.

In another aspect, eye drops and injectable formulations of AMD101 (rifampicin) are provided. AMD101 can only be dissolved in water at about 1.4 mg / ml. However, as provided herein, suitable additives have been used to increase this concentration. These formulations are stable for several weeks.

In another aspect, pharmaceutically acceptable compositions herein, preferably up to about 1% (g / g /).
Composition 100 mL (weight / volume) or (w / v)), or about 0.1% to about 1%, or about 0.25% to about 1%, or about 0.5% to about 1%, or About 0.1% to about 0.5%,
Alternatively, topical eye drop compositions comprising about 0.25% to about 0.5%, or about 0.25%, or about 0.5% rifampicin and at least one pharmaceutically acceptable additive are provided. To.

In one aspect, as used herein, up to about 1% (g / composition 100 mL (weight / volume) or (
w / v)), or about 0.1% to about 1%, or about 0.25% to about 1%, or about 0.5
% To about 1%, or about 0.1% to about 0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0.5% rephanpicin and at least 1. Provided are pharmaceutically acceptable compositions for subcutaneous injection containing one pharmaceutically acceptable additive.

In some embodiments, the pharmaceutically acceptable compositions provided or utilized herein are pH 7-8.5, 7.5-8.0, 7.5-9.0, or 7. .5-12.0. In some embodiments, the pharmaceutically acceptable compositions provided or utilized herein are pH 2.0-7.0, 3.0-7.0, and 4.0-7.0. Is. In some embodiments, the pharmaceutically acceptable composition provided or utilized herein is a physiological salt concentration. In some embodiments, the pharmaceutically acceptable composition provided or utilized herein comprises one or more of antioxidants, preservatives, and other pharmaceutically acceptable additives. Including.

The above overview and detailed description are exemplary and explanatory and are intended to provide further description of the invention set forth in the claims. Other objectives, advantages, and novel features will be readily apparent to those skilled in the art from the detailed description of the invention below.

Histological sections of the retina that induced oxygen-induced retinopathy in the retina and were treated with AMD101 topical eye drops, AMD101 SC injection, and vehicle-only controls, and retinas that did not induce retinopathy are shown. FIG. 1A shows a 200-fold histological section of the retina treated with a medium-only control. FIG. 1B shows a 400-fold histological section of the retina treated with a medium-only control. FIG. 1C shows a 200-fold histological section of the retina treated with the AMD101 topical eye drop formulation. FIG. 1D shows a 400-fold histological section of the retina treated with the AMD101 topical eye drop formulation. Histological sections of the retina that induced oxygen-induced retinopathy in the retina and were treated with AMD101 topical eye drops, AMD101 SC injection, and vehicle-only controls, and retinas that did not induce retinopathy are shown. FIG. 1E shows a 200-fold histological section of the retina treated with AMD101 SC injection. FIG. 1F shows a 400-fold histological section of the retina treated with AMD101 SC injection. FIG. 1G shows a 200-fold histological section of the retina that did not induce retinopathy. FIG. 1H shows a 400-fold histological section of the retina that did not induce retinopathy.

Various embodiments will be described below in the present specification. It should be noted that certain embodiments are not intended as an exhaustive description or as a limitation to the broader aspects described herein. One aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and can be implemented in any other embodiment (s). Descriptions of preferred embodiments, as shown herein and shown in the drawings, are provided solely for illustrative purposes.

Definitions Singular "a", "an" as used herein and in the appended claims.
It should be noted that, and "the" include multiple referents unless explicitly indicated by the context. So, for example, the reference to "solvent (singular)"
Contains multiple such solvents.

As used herein, the term "contains" or "contains" is intended to mean that the composition and method include elements for which the composition and method are listed, but do not exclude others. "In essence consists of", when used to define a composition and method, excludes other elements of any intrinsic importance to the combination for the indicated purpose. means. Thus, a composition or process consisting essentially of the elements defined herein is another material or step that does not substantially affect the basic and new features (s) of the invention set forth in the claims. Do not exclude. "Consists of" means exclusion of trace elements of other components and beyond substantial method steps. The embodiments defined by each of these transition terms are within the scope of the present invention.

Unless otherwise specified, it is understood that all numbers used in the specification and claims to represent the amount of ingredients, reaction conditions, etc. are modified by the term "about" in all cases. Should be. Therefore, unless otherwise specified, the numerical parameters shown in the following specification and the appended claims are approximate values. Each numeric parameter should be interpreted at least in light of the number of significant figures reported and by applying conventional rounding techniques. The term "about" includes (+) or (-) 10%, 5%, or 1% when used in front of numerical representations, such as temperature, time, quantity, and concentration, including range.
Shows an approximate value that can fluctuate.

The combination of substituents and variables is the only one that results in the formation of a stable compound. "
The term "stable", as used herein, is sufficient to be stable enough to enable manufacture and useful for the purposes detailed herein. Refers to a compound that maintains the integrity of the compound for a period of time.

As used herein, a "hydrate" is the form of a compound in which water molecules are combined at a particular ratio as an essential part of the structural complex of the compound.

As used herein, a "solvate" is the form of a compound in which solvent molecules are combined at a particular ratio as an essential part of the structural complex of the compound.

The terms "pharmaceutically acceptable" or "pharmacologically acceptable" as used herein are generally safe, non-toxic, and biologically or otherwise. A composition that is undesirable and does not substantially produce an adverse allergic or immunological response when administered to a host (eg, animal or human). Such formulations include any pharmaceutically acceptable dosage form.

"Pharmaceutically acceptable salt" or "salt thereof" means, as defined above, a salt that is pharmaceutically acceptable and has the desired pharmacological activity. Such salts include organic and inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, etc.
Examples thereof include acid addition salts formed of maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. The base addition salt can be formed of an organic base and an inorganic base such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like. Also included are pharmaceutically acceptable salts or compounds of any of the formulas herein.

The phrase "pharmaceutically acceptable salt", as used herein, refers to a pharmaceutically acceptable organic or inorganic acid or base salt of a compound, depending on its structure. Typical pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, etc.
Water-soluble and water-insoluble salts such as acetate, amsonate (4,5-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzon
ate), bicarbonate, bisulfate, bicarbonate, borate, bromide, butyrate, calcium, calcium edetate, cansilate, carbonate, chloride, citrate, clavaryate (cl)
avulariate), dihydrochloride, edetate, edicylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylalsanylate (avulariate)
glycollylarsanilate), hexafluorophosphate, hexylreso
rcinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate , Mandelate, mesylate,
Methyl bromide, methyl nitrate, methyl sulfate, mutinate, napsilate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy 2-naphthoate, oleate, oxalate,
Palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picphosphate, polygalacturo Acid salt, propionate, ptoluenesulfonate, salicylate,
Stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theocrate, tosylate, triethiodide,
And valerate.

The terms "treat,""treat," or "treat," as used herein, alleviate, relieve, or relieve a disease or condition or one or more symptoms thereof.
Or to improve, to prevent additional symptoms, to improve or prevent the underlying metabolic cause of the symptoms, to prevent the disease or condition, such as to suppress or suppress the onset of the disease or condition, the disease. Alternatively, it is intended to include prevention, including alleviating the condition, causing a relapse of the disease or condition, alleviating the condition caused by the disease or condition, or suppressing the symptoms of the disease or condition. The term also includes alleviating a disease or condition, eg, resulting in a regression of clinical symptoms.
The term further includes achieving therapeutic and / or prophylactic benefits. Therapeutic benefits mean eradication or amelioration of the underlying disorder being treated. Also, the therapeutic benefit is the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder.
It is achieved with improvements in which improvements are observed in the individual, even though the individual is still affected by the underlying disorder. For prophylactic benefit, composition, even if the disease has not been diagnosed, in individuals at risk of developing a particular disease, or in individuals who report one or more of the physiological symptoms of the disease. Administer the substance.

The term "preventing" or "preventing" reduces the risk of acquiring a disease or disorder (ie, may be exposed to or predisposed to the disease, but has not yet experienced the disease. Or to prevent the development of at least one of the clinical symptoms of the disease in subjects who do not show symptoms of the disease). The term further includes preventing the development of clinical symptoms, for example in subjects at risk of suffering from such disease or disorder, thereby substantially preventing the onset of the disease or disorder.

The term "effective amount" refers to an amount that is effective in treating a condition or disorder by nasal administration of the compounds or compositions described herein. In some embodiments, an effective amount of either the composition or dosage form described herein is, in any of the compositions or dosage forms described herein, to a subject in need thereof. An amount used to treat a disorder mediated by hemoglobin, or a disorder that can benefit from tissue and / or cell oxygenation.

The terms "carrier" and "medium" as used herein refer to relatively non-toxic chemical compounds or agents that facilitate the uptake of a compound into cells, such as eye cells, or tissues. Carriers and vehicles useful herein include any such substance known in the art that is non-toxic and does not interact in a detrimental manner with the other components of the formulation in which it is contained. As used herein, "pharmaceutically acceptable carrier" is any and all solvents, dispersion media, coatings, wetting agents (eg sodium lauryl sulfate), isotonic and absorption retarders, disintegration. It contains agents (eg, potato starch or sodium glycolate starch) and the like.

As used herein, a "prodrug" is a compound that, after administration, is metabolized or otherwise converted to an active or more active form for at least one property. To produce a prodrug, a pharmaceutically active compound may be chemically modified to be less active or inactive, but this chemical modification is such that the active form of the compound is metabolized or other organisms. It is like being produced by a scientific process. Prodrugs may have altered metabolic stability or transport characteristics, fewer side effects, or less toxicity compared to this drug. For example, reference Nogrady, 1985, Medicinal Chemistry A Bioch
See emical Approach, Oxford University Press, New York, pages 388-392.
In addition, prodrugs can be prepared using compounds that are not drugs.

The term "eye-acceptable" for formulations, compositions, or ingredients herein is a persistent adverse effect on the treated eye or its function, or on the overall health of the treated subject. It means that it has no effect and shows a transient effect such as a slight stimulus or a "smearing" sensation.

The term "active agent" or "active ingredient" is used herein to refer to a chemical or compound that, when administered to a patient, elicits a desired beneficial effect. Also included are salts, derivatives, and analogs of those compounds or classes of compounds (eg, rifamycin compounds) specifically listed that also elicit the desired effect. For example, "rifamycin", as used herein, comprises a pharmaceutically acceptable salt thereof and a derivative thereof.

The term "buffer" or "buffer" refers to a substance that, when added to a solution, causes the solution to resist changes in pH.

The term "dilution" refers to the formulations or formulations of the invention that use, for example, physiologically equilibrated saline (PBS), such as phosphate buffered saline, or water, or an aqueous system consisting of other water-soluble constituents. Refers to dilution to the desired final concentration, although derived from the formulations of the present invention.

The term "subject" as used herein refers to an organism to be treated with the compositions of the invention. Such organisms include animals (livestock species, wildlife), preferably mammals, including humans and non-humans. The terms patient and subject may be used interchangeably.

The term "surfactant" refers to any molecule that has both a polar head that energetically prefers solvation with water and a hydrophobic tail that is less solvated by water. The surfactant may be ionic or nonionic. The term "ionic surfactant" includes cationic, anionic, and zwitterionic surfactants. The term "cationic surfactant" refers to a surfactant having a cationic head group. "Anionic surfactant"
The term refers to a surfactant having an anionic head group.

"Macular degeneration" refers to various degenerative conditions characterized by loss of central vision due to exacerbation of the macula. One of these conditions is age-related macular degeneration (AMD), which is present in both "dry" and "wet" forms.

"Ocular neovascularization" refers to the abnormal development, proliferation, and / or growth of blood vessels on or in the eye, such as on the surface of the retina.

Methods Some embodiments provided herein are methods of treating visual impairment such as age-related macular degeneration (AMD), ocular angiogenesis, optic neuropathy, glaucoma, optic nerve degeneration, and ophthalmoplegia. explain. Any of the above ophthalmic formulations and / or compounds are useful in the methods described herein.

In some embodiments, a method of treating an eye disease, disorder, injury, or condition is provided, the method of which is a rifamycin compound selected from the group consisting of effective amounts of rifampicin, rifabutin, rifapentine, and rifaximin. Includes administration of an ophthalmic composition comprising: to a patient in need thereof.

In some embodiments, eye disorders, disorders, injuries, or conditions include age-related macular degeneration (AMD), age-related macular degeneration (AMD), retinal ganglion, chronic glaucoma, retinal detachment, sacral erythrocytosis, Cell injury, iris angiogenesis, inflammatory disease, chronic vasculitis, neoplasm, Fuchs iris achromatic iris styroiditis, angiogenic glaucoma, corneal angiogenesis, choroidal angiogenesis, retinal angiogenesis, retinal hematoma proliferation, etc. Selected from the group consisting of.

In some embodiments, a method of treating angiogenesis of the eye is provided, the method of which comprises an ophthalmic composition comprising an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin. Includes administration to patients in need of it. In some embodiments, the procedure reduces or reverses secondary vision loss to angiogenesis of the cornea, iris, retina, or choroid. In some embodiments,
Ocular angiogenesis is a combination of vitrectomy and lens resection, retinal ischemia, choroidal hemorrhage disorder, choroidal thrombosis, angiogenesis after carotid ischemia, optic nerve angiogenesis, and ocular penetration or bruising. Includes angiogenesis for sexual eye injury.

In some embodiments, a method of treating age-related macular degeneration (AMD) is provided, the method comprising a therapeutically effective amount of a rifampycin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin. Includes administering an ophthalmic composition to a patient in need thereof. In some embodiments, this method is dry AM.
Includes treatment of D. In other embodiments, the method comprises the treatment of wet AMD.

In some embodiments, a method of treating retinal neovascularization is provided, the method of which is an ophthalmic composition comprising a therapeutically effective amount of a rifampycin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin. Includes administration to patients in need of it.

In some embodiments, a method of protecting optic nerve cells is provided, the method comprising an ophthalmic composition comprising a therapeutically effective amount of a rifampycin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin. , Including administration to patients in need of it. In some embodiments, the optic nerve cell is a retinal ganglion cell.

In some embodiments, a method of inhibiting brain damage is provided, the method comprising an ophthalmic composition comprising a therapeutically effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin. , Including administration to patients in need of it.

In some embodiments of the method, the rifampicin compound is rifampicin.
In some embodiments, the rifamycin compound is rifabutin. In some embodiments, the rifapentine compound is rifapentine. In some embodiments, the rifaximin compound is rifaximin. In some embodiments, the ophthalmic composition is at least one of a nonionic tonicity modifier, a salt, a preservative, a buffer, a surfactant, an antioxidant, a solubilizer, and a stabilizer. Including further. In some embodiments, the composition is administered topically. In some embodiments, the composition is in the form of eye drops, gels, lotions, creams, or ointments, or is incorporated into conformers, implants, stents, or ophthalmic spray drug delivery devices.

The compounds and pharmaceutical compositions of the present invention may be used alone or in combination with other compounds. When administered with another agent, co-administration may be in any manner such that both pharmacological effects appear in the patient at the same time. Thus, co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for the administration of both the compounds of the invention and other agents, or two of these. The agent does not need to be administered exactly at the same time. However, co-administration is most conveniently achieved at substantially the same time by the same dosage form and the same route of administration. Obviously, such administration proceeds most advantageously by simultaneously delivering both active ingredients in the novel pharmaceutical composition according to the invention.

In some embodiments, in addition to administration of the ophthalmic composition, the method comprises oral administration of an effective amount of the active ingredient (eg, a riffamycin compound). Suitable oral formulations of rifamycin compounds selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin are known in the art. Therefore, the method involves the patient via any suitable mode of administration in which the active ingredient (eg, a riffamycin compound) is topical, ocular, oral, subcutaneous, mucosal, intradermal, intranasal, cheek, sublingual, lung, etc. Includes combination treatments administered to.

The effective amount of the riffamycin compound is the amount required to produce a protective effect in vitro or in vivo. In some embodiments, the effective amount in vitro is about 0.
It is 1 nM to about 1 mM. In some embodiments, the effective amount in vitro is about 0.1.
nM to about 0.5 nM, or about 0.5 nM to about 1.0 nM, or about 1.0 nM to about 5.
0 nM, or about 5.0 nM to about 10 nM, or about 10 nM to about 50 nM, or about 5
0 nM to about 100 nM, or about 100 nM to about 500 nM, or about 500 nM to about 1
It is mM. In some embodiments, the effective amount for the effect in vivo is about 0.1 m.
g to about 100 mg, or preferably about 1 mg to about 50 mg, or more preferably about 1
It is from mg to about 25 mg / kg / day, or from about 1 mg to about 12 mg / kg / day. In some other embodiments, the effective amount in vivo is from about 10 mg / kg / day to about 100 mg / k.
g / day, about 20 mg / kg / day to about 90 mg / kg / day, about 30 mg / kg / day to about 80
mg / kg / day, about 40 mg / kg / day to about 70 mg / kg / day, or about 50 mg / k
It is from g / day to about 60 mg / kg / day. In some embodiments, the effective amount in vivo is from about 1 mg / kg / day to about 5 mg / kg / day. In some embodiments, the effective amount in vivo is from about 6 mg / kg / day to about 12 mg / kg / day. In one embodiment, the effective amount in vivo is about 3 mg / kg / day. In another embodiment the effective amount in vivo is about 6 mg / kg / day. In another embodiment, the effective amount in vivo is about 12 m.
It is g / kg / day. In yet some other embodiments, the effective amount in vivo is about 1
It ranges from 00 mg / kg / day to about 1000 mg / kg / day.

Composition In one aspect, a composition comprising an effective amount of a riffamycin compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, preferably an ophthalmic composition, is provided herein.

Rifamycin class antibiotics were originally isolated from cultures of Streptomyces mediterranei. With a large number of available analogs and derivatives that are synthetically produced
Rifamycin is widely used in the removal of pathogenic bacteria that have become resistant to commonly used antibiotics.

Rifamycin is primarily effective against mycobacteria and therefore tuberculosis (TB)
, Hansen's disease, and used to treat chronic infections, including Mycobacterium avium complex (MAC) infections. In addition to its effects on the lungs, TB is also known to affect other organs, including eye tissue. Therefore, the effects of riffamycin on TB and other eye disorders of the eye are being studied. Monitoring chronic administration of rifampicin in HCV patients was observed to strongly inhibit the liver cancer marker alpha-fetoprotein. Rifampicin has a strong angiogenic effect, which leads to VEGF, HGF
Major angiogenic genes such as are strongly inhibited.

Suitable rifamycin compounds include, for example, rifampicin (rifabutin), rifabutin, rifapentine, rifalazil, and rifaximin, or pharmaceutically acceptable salts thereof, or derivatives thereof. Synthesis of simple rifamycin derivatives is well known in the art, such as rifampicin (US Pat. No. 3,342,810), rifabutin (US Pat. No. 4,219,478), and rifalazil (US Pat. No. 4,219,478). U.S. Pat. No. 4,9
The synthesis of (8,602) is known in the art and is incorporated herein by reference.

In some embodiments, in the present specification, a composition comprising an effective amount of a riffamycin compound or a pharmaceutically acceptable salt thereof and an inert non-eye-irritating, non-toxic eye drop carrier, preferably for ophthalmology. Compositions or eye drop compositions are provided. Such carriers are well known, such as Phys.
ician's Desk Reference for Ophthalmology (1982 Edition, published by Medical Eco
Commonly referred to in nomics Company, Inc., Oridell, New Jersey), many sterile ophthalmic ophthalmic solutions have been reported in this document, see pages 112-114, for example. Incorporated by.

In some embodiments, the compositions comprising the ophthalmic compositions described herein are ophthalmic solutions, suspensions, gels such as eye drops, solutions, contact lens solutions, etc. intended for ophthalmic use, for example. , Cream, and ointment. In some embodiments, the eye drops are administered by eye drops. In some embodiments, the ophthalmic composition is in the form of topical eye drops. In one embodiment, the ophthalmic composition is a solution. In another embodiment, the ophthalmic composition is a suspension.

In some embodiments, the composition, including the ophthalmic composition, is included in various drug delivery systems known in the art. For example, the composition may be included in an ocular solution used to clean, store, soak, or soak contact lenses. Soft contact lenses containing bodies formed from hydrophilic gel materials such as 2-hydroxyethyl methacrylate (HEMA) and ophthalmic solutions for cleaning or immersing them are known and commercially available in the art. There is. In one embodiment, the ophthalmic composition is incorporated into an ophthalmic solution used to immerse and swell a hydrophilic gel-containing lens. The lens absorbs the solution containing the active ingredient and slowly releases it upon insertion into the eye. Therefore, a therapeutically effective dose of the active ingredient, the riffamycin compound, is delivered to the patient wearing contact lenses. In one embodiment, the contact lens may be re-immersed in an ophthalmic solution containing a therapeutic level of active ingredient to replace the drug after use in the eye. In some embodiments, the active ingredient can be dispersed into the lens matrix via a polymerization medium.

In some embodiments, the concentrations of the riffamycin compound herein are from about 0.01% to about 50% by weight, from about 0.05% to about 40% by weight, from about 0.1% by weight. About 30% by weight
, About 0.5% by weight to about 20% by weight, about 1.0% by weight to about 10% by weight, about 1.5% by weight to about 5% by weight, about 2.0% by weight to about 3.0% by weight. , And a composition comprising an ophthalmic composition having a range between any two of these values, or less than any one of these values. In some embodiments, the ophthalmic composition is about 50% by weight, 30% by weight, 20% by weight, 1
0% by weight, about 8% by weight, about 7% by weight, about 5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1 Includes 5.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.05% by weight of riffamycin compounds.

In some embodiments, the composition comprising the ophthalmic composition comprises a medium. Examples of suitable media for this ophthalmic composition include, but are not limited to, purified water and vegetable oils (eg, olive oil, castor oil, sesame oil, etc.).

In some embodiments, the composition comprising the ophthalmic composition further comprises one or more tonicity regulators. In some embodiments, the tonicity regulator is saline. Suitable tonicity modifiers are known in the art and include, but are not limited to, sodium chloride, potassium chloride, buffer salts, dextrins, glycerin, propylene glycol, and mannitol.

In some embodiments, the composition comprising the ophthalmic composition optionally comprises one or more surfactants. In some embodiments, the nonionic surfactant assists in dispersing the active ingredient (eg, a riffamycin compound) in the suspension and improves solution clarity. Suitable surfactants are known in the art and are sorbitan ether esters of oleic acid (eg polysolvate 80 or Tween 20 and 80), polyoxyethylene hydrogenated castor oil, cremofol, sodium alkylbenzene sulfonate, glycerol, lecithin, sucrose. Examples include, but are not limited to, esters, polyoxyethylene alkyl ethers, polyoxyl stearate, polyoxyl 40 stearate, polymers of oxyethylated octylphenol (tyroxalol) and polyoxyethylene polyoxypropylene glycol, or combinations thereof. In some embodiments, the ophthalmic composition comprises polysorbate 80, polyoxyethylene hydrogenated castor oil, lecithin, or a combination thereof. In some embodiments, the amount of surfactant in the composition is
It is about 0.1 to about 50% by weight, about 0.5 to about 40% by weight, about 0.1 to about 30% by weight, about 1 to about 20% by weight, and about 2 to about 10% by weight. In some embodiments, the ophthalmic composition is
About 0.01% by weight to 20% by weight, about 0.1% by weight to 15% by weight, about 0.15% by weight to 10% by weight
By weight%, about 0.2% by weight to 5% by weight, about 0.25% by weight to 3% by weight, about 0.3% by weight to 2
Weight%, about 0.1% to 20% by weight, about 1% to 10% by weight, about 2% to 10% by weight, about 2% to 8% by weight, about 2% to 5% by weight, Includes about 5% to 10% by weight and about 5% to 20% by weight of surfactant. In some embodiments, the ophthalmic composition comprises polysorbate 80, twenty80, twoen20, polyoxyethylene hydrogenated castor oil,
And lecithin, or a combination thereof, selected from about 0.1% by weight to 10% by weight.
Contains surfactants.

In some embodiments, the composition comprising the ophthalmic composition may optionally comprise a stabilizer or antioxidant. Suitable stabilizers and antioxidants are known in the art and are ascorbic acid salt, ascorbic acid, isoascorbic acid, sodium glutathione bisulfite, sodium metabisulfite, acetylcysteine, 8-hydroxyquinoline, thiourea, tocopherol. , EDTA, sodium sulfide sulfite dihydrate, and combinations thereof, but are not limited thereto. In some embodiments, the ophthalmic composition is about 0.01% to 20% by weight, about 0.1% to 15% by weight, about 0.15% to 10% by weight, about 0. 2% to 5% by weight, about 0.25% to 3% by weight, about 0.3% to 2% by weight, about 0.1% to 20% by weight, about 1% to 10% by weight, About 2% by weight ~
10% by weight, about 2% to 8% by weight, about 2% to 5% by weight, about 5% to 10% by weight,
Includes about 5% to 20% by weight of antioxidants or stabilizers. In some embodiments, the ophthalmic composition comprises from about 0.01% to 10% by weight of antioxidant or stabilizer.

In some embodiments, the composition comprising the ophthalmic composition may optionally comprise a lubricant.
Examples of suitable lubricants include, but are not limited to, glycerol, hydroxypropylmethylcellulose, carboxypropylmethylcellulose, sorbitol, polyvinylpyrrolidone, polyethylene glycol, polyvinyl acetate, and combinations thereof. In some embodiments, the ophthalmic composition is about 0.01% to 20% by weight.
About 0.1% to 15% by weight, about 0.15% to 10% by weight, about 0.2% to 5% by weight, about 0.25% to 3% by weight, about 0.3% by weight ~ 2% by weight, about 0.1% by weight to 20% by weight, about 1% by weight to 10% by weight, about 2% by weight to 10% by weight, about 2% by weight to 8% by weight, about 2
Includes about 5% to 5% by weight, about 5% to 10% by weight, and about 5% to 20% by weight of lubricant.
In some embodiments, the ophthalmic composition comprises from about 0.01% to 10% by weight of lubricant.

In some embodiments, the composition, including the ophthalmic composition, is optionally detargeted.
A turgescent) agent may be included. Examples of suitable detargeting agents include low or high molecular weight polysaccharides such as dextran, dextran sulfate, polyvinylpyrrolidone, polyethylene glycol, polyvinyl acetate, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxypropylmethylcellulose, dextrose, sucrose, and others. sugar,
And combinations thereof, but are not limited to these. Dextran 40,
Any suitable molecular weight dextran or mixture thereof may be used, including dextran 70 and / or dextran 500. In some embodiments, the ophthalmic composition is about 0.01% to 20% by weight, about 0.1% to 15% by weight, about 0.15% to 10% by weight, about 0. 2% to 5% by weight, about 0.25% to 3% by weight, about 0.3% to 2% by weight, about 0.1% to 20% by weight, about 1% to 10% by weight, About 2% by weight ~
10% by weight, about 2% to 8% by weight, about 2% to 5% by weight, about 5% to 10% by weight,
Includes about 5% to 20% by weight detargetant. In some embodiments, the ophthalmic composition comprises from about 0.01% to 10% by weight of detagecent.

In some embodiments, the composition comprising the ophthalmic composition may further comprise one or more viscosity-imparting agents. In some embodiments, the viscosity-imparting agent increases the viscosity of the ophthalmic solution and suspension. In some embodiments, the viscosity-imparting agent increases eye contact time, thereby reducing drainage rates. In some embodiments, the viscosity-imparting agent increases mucosal adhesion, ocular bioavailability, and / or provides a lubricating effect. As an example of a suitable viscosity imparting agent, a carboxyvinyl polymer (eg Carbopol 934P or 97)
4P), cellulosic polymers (eg, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, etc.), polysaccharides (eg, xanthan gum), polyvinylpyrrolidone, polyvinyl alcohol, and combinations thereof, but are not limited thereto. In some embodiments, the ophthalmic composition is about 0.0.
1% by weight to 20% by weight, about 0.1% by weight to 15% by weight, about 0.15% by weight to 10% by weight,
About 0.2% to 5% by weight, about 0.25% to 3% by weight, about 0.3% to 2% by weight,
About 0.1% by weight to 20% by weight, about 1% by weight to 10% by weight, about 2% by weight to 10% by weight, about 2
Weight% to 8% by weight, about 2% to 5% by weight, about 5% to 10% by weight, about 5% to 20% by weight
Contains% by weight of viscosity imparting agent. In some embodiments, the ophthalmic composition comprises from about 0.01% to 10% by weight of a viscosity-imparting agent.

In some embodiments, the composition comprising the ophthalmic composition may comprise one or more phospholipid compounds. Suitable phospholipids are known in the art and are small alkyl chain phosphatidyllipids, phosphatidylcholine, egg phosphatidylcholine, soyphosphatidylcholine, dipalmitylphosphatidylcholine, soyphosphatidylglycerol, egg phosphatidylglycerol, distearoylphosphatidylglycerol, dimyristylphosphatidylcholine , Dilaurylphosphatidylcholine, 1-myristoyl-2-palmitoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, 1-palmitoyl-2-stearoylphosphatidylcholine,
1-stearoyl-2-palmitoylphosphatidylcholine, dioleoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1-oleoil-
2-Palmitylphosphatidylcholine, dioleoylphosphatidylethanolamine,
Dilauroylphosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol, dimiristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioreoil phosphatidylglycerol, phosphatidyl phosphatidyl , Dipalmityl phosphatidylseric acid, dimyristoyl phosphatidylethanolamine, dipalmityl phosphatidylethanolamine, dimyristoyl phosphatidylserine, dipalmityl phosphatidylserine, brain phosphatidylserine, sphingomierin, sphingolipid, brain sphingomierin, dipalmityls Myerin, galactocelebroside, ganglioside, celeroside, phosphatidylglycerol, phosphatidylic acid, phosphatidyl, lysophosphatidylethanolamine, cephalin, cardiolipin, disetyl phosphate, distearoyl-phosphatidylethanolamine, or combinations thereof. .. Further, the phospholipid may be a derivative or analog of any of the above phospholipids. In some embodiments, the ophthalmic composition is about 0.01% to 20% by weight, about 0.
1% to 15% by weight, about 0.15% to 10% by weight, about 0.2% to 5% by weight, about 0.25% to 3% by weight, about 0.3% to 2% by weight %, Approximately 0.1% by weight to 20% by weight,
About 1% by weight to 10% by weight, about 2% to 10% by weight, about 2% to 8% by weight, about 2% by weight
Includes ~ 5% by weight, about 5% by weight to 10% by weight, and about 5% to 20% by weight of phospholipid compounds. In some embodiments, the ophthalmic composition comprises from about 0.01% to 10% by weight of the phospholipid compound.

In some embodiments, the composition comprising the ophthalmic composition may optionally include a preservative.
Examples of preservatives include imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, EDTA disodium, thimerosal, chlorobutanol sorbic acid,
And combinations thereof, but are not limited to these. In some embodiments, the ophthalmic composition is about 0.01% to 20% by weight, about 0.1% to 15% by weight.
, About 0.15% by weight to 10% by weight, about 0.2% by weight to 5% by weight, about 0.25% by weight to 3% by weight, about 0.3% by weight to 2% by weight, about 0.1% by weight. % To 20% by weight, about 1% to 10% by weight, about 2% to 10% by weight, about 2% to 8% by weight, about 2% to 5% by weight, about 5% to 10% by weight , Approximately 5% to 20% by weight of preservative. In some embodiments, the ophthalmic composition comprises from about 0.01% to 10% by weight of preservative.

In some embodiments, the composition comprising the ophthalmic composition optionally comprises one or more buffers that keep the pH of the composition within the generally acceptable range for the eye drop composition. Good. In some embodiments, the composition has a pH of about 4-8, preferably 3-7.5, or about 7.
Is buffered in. In some embodiments, the pH range is from about 6.8 to about 7.8. Examples of suitable buffers include acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, etc. Citrate, which comprises a base; and a buffer such as citrate / dextrose, sodium bicarbonate and ammonium chloride, and combinations thereof.
Phosphates, borates, bicarbonates, sodium salts, potassium, but not limited to these. The acids, bases, and buffers are included in amounts necessary to keep the pH of the composition within the acceptable range for the eye.

Compositions containing ophthalmic compositions may additionally comprise a suitable diluent known in the art. In some embodiments, the diluent is an isotonic eye treatment carrier buffered to a suitable pH, eg, in the range of about 4.0 to about 8.0, with an effective amount of wetting agent and Contains antibacterial agents.

The components of the composition, including the ophthalmic composition described above, are about 0.001% by weight, if present.
About 0.01% by weight, about 0.02% by weight, about 0.05% by weight, about 0.1% by weight, about 0.5% by weight, about 1.0% by weight, about 2% by weight, about 5% by weight %, About 10.0% by weight, about 15.0% by weight
, About 20.0% by weight, about 30.0% by weight, about 40.0% by weight, about 50.0% by weight, about 60
.. Compositions in the range of 0% by weight, about 70.0% by weight, about 90.0% by weight, and in the range between any two of these values, or at concentrations lower than any one of these values. It may be incorporated into an object.

Compositions containing ophthalmic compositions can be produced by methods known in the art. For example, the active ingredient, i.e. the riffamycin compound, is dissolved in purified water or saline, and a surfactant is added to it and mixed. Additional additives such as isotonic agents such as sodium chloride and glycerin, buffers such as sodium phosphate or sodium borate, pH regulators such as dilute hydrochloric acid and sodium hydroxide, preservatives such as potassium sorbate, tocopherols,
An antioxidant such as ascorbic acid is optionally added to this mixture to obtain an ophthalmic composition.

Compositions, including ophthalmic compositions, are tested for a variety of physicochemical, in vitro, and in vivo properties. Transparency is measured using visual and fluorescence microscopy. Also,
The presence of particulate matter is measured to ensure that the ophthalmic solution is free of foreign particles. Light shielding or microscopy is used for counting and / or measuring particle size. The isotonicity and pH of the composition are tested.

The drug content of the ophthalmic composition is evaluated by suitable analytical methods such as UV and HPLC. The composition is also tested for preservative efficacy, stability, and shelf life according to standard guidelines. The composition can be further sterilized using various sterilization methods known in the art.

The compositions of the present invention are tested for a variety of physicochemical, in vitro, and in vivo properties. For example, compositions are evaluated for inhibition of gene expression of angiogenic genes and protection of retinal ganglion cells in vitro using suitable methods known in the art.

The ophthalmic composition of the present invention is expected to have high efficiency and show high affinity for mucosal tissues including the eyeball. Some embodiments described herein relate to compositions that deliver a therapeutically effective amount of a drug through the mucosa into the systemic circulation. In some embodiments, the compositions of the invention are, but not limited to, avoiding first-pass metabolism of the drug (s), avoiding irritation of the GI mucosa, avoiding fluctuations in drug levels, predictable. Active period and extension of active period,
Minimize unwanted side effects, compatibility of drugs with short half-life and narrow therapeutic index, maintain stable plasma concentration of strong drugs, eliminate multiple doses and dosage forms (oral and systemic) Increased patient compliance by doing so, no need for local anesthesia, no pain associated with injections, ease of administration, suitability for self-administration, and ease of termination of treatment at any time It provides advantages over other types of routes of administration, including, such as oral, intravitreal, etc.

In some embodiments, the present specification provides ophthalmic compositions for use in the manufacture of a medicament for treating an eye or visual impairment. In some embodiments, the eye disease, disorder, or condition is selected from age-related macular degeneration (AMD), ocular angiogenesis, retinal ganglion cell injury, and brain injury.

In some embodiments, eye disorders, disorders, comprising those selected herein from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, and at least one pharmaceutically acceptable carrier substance. Alternatively, a formulation for the treatment of the condition is provided. In some embodiments, the carrier material comprises an ophthalmic / ophthalmic carrier. Suitable ophthalmic / ophthalmic carrier materials are known in the art and include solutions, gels, ointments and the like. In some embodiments, the ophthalmic / ophthalmic carrier is a sterile aqueous solution. In some embodiments, the present formulation further comprises one or more of surfactants, antibacterial agents, pH buffers, antioxidants, preservatives, or combinations thereof.

In some embodiments, the present specification provides a composition comprising an ophthalmic composition for the treatment of age-related macular degeneration, such composition from effective amounts of rifampicin, rifabutin, rifapentine, and rifaximin. Contains rifampicin compounds selected from the group.

In some embodiments, the present specification provides a composition comprising an ophthalmic composition for the treatment of retinal neovascularization, which composition comprises effective amounts of rifampicin, rifabutin, rifapentine, and rifaximin. Contains rifampicin compounds selected from the group.

In some embodiments, the present specification provides a composition comprising an ophthalmic composition for protecting optic nerve cells, the composition comprising an effective amount of rifampicin, rifabutin, rifapentine, and rifaximin. Contains rifampicin compounds selected from.

In some embodiments, the present specification provides a composition comprising an ophthalmic composition for inhibiting brain injury, the composition comprising an effective amount of rifampicin, rifabutin, rifapentine, and rifaximin. Contains rifampicin compounds selected from.

In another embodiment, there is provided herein a composition comprising a stabilized ophthalmic composition comprising a riffamycin compound, wherein the composition is greater than 3 months, preferably greater than 6 months. It is preferably stable over 12 months.
Example

Eye drop formulation of rifamycin compound The active ingredient, namely rifampicin, rifabutin, rifapentine, rifalazil, or rifaximin, is dissolved in saline or water and polysorbate 80, tween8.
Add and mix surfactants such as 0 or ween 20. In addition, various additives such as glycerin, xanthan gum, hydroxypropyl methylcellulose (HPM)
C), cyclodextrin derivatives such as hydroxypropyl-β-cyclodextrin, isotonic agents such as sodium chloride, potassium chloride, or sodium bicarbonate, preservatives such as EDTA disodium or methylparaben, antioxidants such as ascorbic acid. Arbitrarily added and mixed to form a clear solution. This solution is optionally filtered to remove particulate matter.
The pH is adjusted by adding an acid such as hydrochloric acid or a base such as sodium chloride to obtain a desired pH.

As disclosed in Tables 1-3, 16 different formulations were prepared for topical eye drop application of rifampicin. The formulations of Example 1A and Example 6A were used in the following studies.

The following eye drop formulations were prepared at room temperature (Tables 1 and 2) and rifampicin was added to the eye drop formulations to the final concentrations listed.

During the eye drop formulations of Examples 1A and 5A-8A listed in Tables 1 and 2, rifampicin was completely dissolved at room temperature and rifampicin did not precipitate in these formulations for several weeks. The rifampicin solution was stored at room temperature or in the refrigerator.

The input buffer added in Examples 1A-10A is 50 mM boric acid-borax or 100.
It is mM boric acid-NaOH, and the pH values of these input buffers are listed in Tables 1 and 2.
A liquid formulation was prepared by mixing the components listed in the table, rifampicin powder was added to this formulation and mixed for 2-3 hours. After mixing rifampicin in the prescription, p
The values of H were measured and these pH values were listed in the table.

The buffers listed in Table 3, NaCl, Tween80, and EDTA were mixed in a beaker at room temperature, rifampicin was added, and they were completely dissolved in these liquid formulations at room temperature. A stock solution of formaldehyde sulfoxylate dihydrate or L-ascorbic acid was added to this formulation and then the pH value in this formulation was measured (Examples 11A-
16A). The formulations of Examples 11A and 12A were stable at room temperature for more than a few days and they did not produce any precipitate. The formulations of Examples 13A-16A were stable in the refrigerator for more than a few days and they did not produce any precipitate.

Rifampicin was delivered to the retina by topical eye drop application. A 0.25% rifampicin eye drop formulation was used for these studies. Exhibiting excellent delivery efficiency, the retinal tissue obtained microgram concentration of rifampicin per gram of tissue by applying this eye drop.

Four male Sprague-Dawley rats (250-300 g) were used to measure retinal exposure levels of rifampicin after eye drop application. Two rats, each eye under isoflurane sedation, an eye drop formulation (0.2) shown as Example 1A listed in Table 1.
3 drops of 5% rifampicin) were given. The remaining two rats were given 10 drops of the same application to each eye under isoflurane sedation. One drop contained 5 μL of the above formulation and each drop was applied at 30 minute intervals. After applying the eye drops, the retina was removed under an anatomical microscope. in addition,
A "non-treated" negative control was taken and the retinas were removed from 2 rats without any treatment. Retinas were placed in a 1.5 ml microcentrifuge tube (1 retina / tube) and extensively washed with DPBS. After the washing procedure, the retinal tissue in a microcentrifuge tube was frozen in dry ice and stored for quantification by LC / MS analysis. Table 4 shows the quantification of rifampicin extracted from retinal tissue. Rifampicin was delivered to the retina in a dose-dependent manner by eye drop prescription (0.25% rifampicin).

Retinal delivery efficiency of AMD101 by eye drop prescription> 100 times higher than dexamethasone retinal delivery

This example provides the experimental procedure and results of a PK study showing that rifampicin is delivered to the retina by subcutaneous (SC) injection. The amounts detected with SC and topical eye drops were comparable.

Six male Sprague-Dawley rats (250-300 g) were used to measure retinal exposure levels of rifampicin after subcutaneous injection (20 mg / Kg). Using the formulations shown as Example 6A listed in Table 2, rifampicin was administered by SC injection in this study. At 1, 3, and 7 hours after SC injection, retinal tissue was removed from the rat under an anatomical microscope. In addition, "untreated" negative controls were taken and retinas were removed from 2 rats without any treatment. Retinas were placed in a 1.5 ml microcentrifuge tube (1 retina / tube) and extensively washed with DPBS. After the washing procedure, the retinal tissue in a microcentrifuge tube was frozen in dry ice and stored for quantification by LC / MS analysis. Table 5 shows the quantification of rifampicin extracted from retinal tissue. The amount detected in the retina by SC injection was comparable to the amount delivered by the eye drop formulation (see Table 3).

Experimental procedures and results for PK studies using a 0.25% rifampicin eye drop formulation were provided.

Six male Sprague-Dawley rats (250-300 g) were used to measure retinal exposure levels of rifampicin after topical eye drop application. The compound was administered to one eye of the rat using 15 μL of the eye drop formulation shown as Example 1A listed in Table 1.
15 μL of the above formulation contained 37.5 μg of rifampicin. Retinal tissue was removed from the rat under an anatomical microscope at 1 hour, 3 hours, and 7 hours after application of the eye drops. In addition, a "non-treated" negative control was taken and the retina was removed from one rat without any treatment. Retinas were placed in a 1.5 ml microcentrifuge tube (1 retina / tube) and extensively washed with DPBS. After the washing procedure, the retinal tissue in a microcentrifuge tube was frozen in dry ice and stored for quantification by LC / MS analysis. Table 6 shows the quantification of rifampicin extracted from retinal tissue. Rifampicin was delivered to the retina by an eye drop prescription (0.25% rifampicin).

Experimental procedures and results of dose response studies using 0.25% and 0.5% rifampicin eye drop formulations were provided.

Four male Sprague-Dawley rats (250-300 g) were used to measure retinal exposure levels of rifampicin after topical eye drop application. The compounds were administered to one eye of the rat using 15 μL of the eye drop formulation shown as Examples 1A and 6A listed in Tables 1 and 2, respectively. The 15 μL of the above formulation was 37.5 and 75, respectively.
It contained μg of rifampicin. One hour after applying the eye drops, retinal tissue was removed from the rat under an anatomical microscope. In addition, a "non-treated" negative control was taken and the retina was removed from one rat without any treatment. Retinas were placed in a 1.5 ml microcentrifuge tube (1 retina / tube) and extensively washed with DPBS. After the washing procedure, the retinal tissue in a microcentrifuge tube was frozen in dry ice and stored for quantification by LC / MS analysis. Table 7 shows the quantification of rifampicin extracted from retinal tissue. Rifampicin was delivered to the retina in a dose-responsive manner by both eye drop formulations (0.25% and 0.5% rifampicin).

An experimental procedure for preclinical efficacy studies in a rat model of oxygen-induced retinopathy using a 0.25% rifampicin eye drop formulation was provided.

Rat models of oxygen-induced retinopathy were described by Yanni et al. (2010) and Dorfmann et al. (
It was prepared according to the protocol of 2008). Sprague-Dawley rat pups (
And their lactating mother rats) were exposed to the circulating oxygen environment (80% and 21%, about 1 day each) for 15 days starting from the day of birth (day 0). On the 15th day (P15), the animals were moved into the room air. Six pups, seven pups, and six pups were assigned to the vehicle-only controls, AMD101 (rifampicin) eye drop prescription, and SC injection groups, respectively.
Only the eye drop formulations or media shown as Example 1A listed in Table 1 are used from P15 to P1.
It was administered daily to the eyes of pups for 5 days between 9 in the morning, around noon, and in the evening. 20 mg once daily on P15-P19 using the formulations shown as Example 6A listed in Table 2.
AMD101 (rifampicin) was administered to pups by SC injection of / Kg. P20
All animals were anesthetized and the retina was visualized in histological sections. In those histological sections, in retinal tissue in 3 eyes (AMD101 topical application, AMD101 SC injection administration group, and non-retinopathy-induced) or 5 eyeballs (medium-only control administration group) Angiogenesis was quantified by counting the capillaries of the retina. These eyes were selected from a variety of animals in the above-mentioned dosing group. Representative histological section images are shown (FIGS. 1A-H). Retinas treated with medium-only controls showed an increased number of small new capillaries on the surface of the retina (see FIGS. 1A and 1B). Retinas treated with the AMD101 topical eye drop formulation showed small growth foci of new capillaries on the surface of the retina, but fewer than in the control group (see Figures 1C and 1D). Retinas treated with AMD101 SC injection showed small growth foci of new capillaries on the surface of the retina, but fewer than in the control group (see Figures 1E and 1F).
The retina without retinopathy showed some small vessel cross-sections, but no new capillaries (see Figures 1G and 1H). Table 8 shows the quantification of capillaries detected in histological sections.

Delivery of ophthalmic formulations of refamycin compounds via devices such as contact lenses.

Immerse or wash contact lenses with an ophthalmic formulation containing the active ingredient, namely rifampicin, rifabutin, rifapentine, rifalazil, or rifaximin, and a pharmaceutically acceptable carrier, and optionally the additives disclosed herein. Incorporate into the ophthalmic solution used to. Contact lenses made of hydrophilic gel are optionally dried at ambient temperature and then soaked in a solution of dipping or swelling agent containing an effective amount of ophthalmic formulation, washed or soaked.

It will be apparent to those skilled in the art that various modifications and modifications can be made in the methods and compositions of the invention without departing from the spirit or scope of the invention. Accordingly, the present invention is intended to include as long as the modifications and modifications of the present invention fall within the appended claims and their equivalents.

Claims (27)

An ophthalmic composition comprising an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, may be administered to a patient in need thereof. Methods of treating eye disorders, disorders, or conditions, including. The method of claim 1, wherein the eye disease, disorder, or condition is selected from age-related macular degeneration (AMD), ocular angiogenesis, retinal ganglion cell injury, and brain injury. Administering a therapeutically effective amount of an ophthalmic composition comprising a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, to patients in need thereof. Age-related macular degeneration (AMD), including
) How to treat. Administering a therapeutically effective amount of an ophthalmic composition comprising a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, to patients in need thereof. Methods of treating ocular neovascularization, including. The method of claim 4, wherein the ocular neovascularization comprises retinal angiogenesis. Administering a therapeutically effective amount of an ophthalmic composition comprising a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Methods of protecting optic nerve cells, including. The method of claim 6, wherein the optic nerve cell is a retinal ganglion cell. Administering a therapeutically effective amount of an ophthalmic composition comprising a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Methods of inhibiting brain damage, including. An ophthalmic composition comprising an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The ophthalmic composition according to claim 9, wherein the pharmaceutically acceptable carrier comprises a tonicity regulator. The ophthalmic composition according to claim 10, wherein the tonicity adjusting agent is a saline solution, dextrose, glycerin, an aqueous potassium chloride solution, a buffer salt, propylene glycol, or mannitol. The ophthalmic composition according to claim 10, which is in the form of a topical eye drop. The ophthalmic composition according to any one of claims 10 to 12, for use in the manufacture of a medicament for the treatment of an eye disease, disorder, or condition. The ophthalmic composition according to claim 13, wherein the eye disease, disorder, or condition is selected from age-related macular degeneration (AMD), ocular angiogenesis, retinal ganglion cell injury, and brain injury. Formulations for the treatment of eye diseases, disorders or conditions, comprising effective amounts of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, and at least one pharmaceutically acceptable carrier substance. .. The preparation according to claim 15, wherein the carrier substance comprises an ophthalmic / ophthalmic carrier. The preparation according to claim 15, further comprising one or more of a surfactant, an antibacterial agent, a pH buffer, an antioxidant, a preservative, or a combination thereof. Up to about 1% (g / composition 100 mL, or weight / volume, or (w / v)), or about 0.1% to about 1%, or about 0.25% to the eye of a patient, including the retina. About 1%, or about 0
.. 5% to about 1%, or about 0.1% to about 0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0.5% retina, and A method of inhibiting ocular neovascularization in the retina of said patient in need thereof comprising topically administering a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable additive. Up to about 1% (g / composition 100 mL, weight / volume, or (w / v)), or about 0.
1% to about 1%, or about 0.25% to about 1%, or about 0.5% to about 1%, or about 0.
1% to about 0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0
.. A pharmaceutically acceptable topical eye drop composition comprising 5% rifampicin and at least one pharmaceutically acceptable additive. Up to about 1% (g / composition 100 mL, weight / volume, or (w / v)), or about 0.
1% to about 1%, or about 0.25% to about 1%, or about 0.5% to about 1%, or about 0.
1% to about 0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0
.. A pharmaceutically acceptable subcutaneous injection composition comprising 5% rifampicin and at least one pharmaceutically acceptable additive. It is necessary, including administering to the patient an ophthalmic composition comprising an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof. A method for reducing the thickness of the retina in the patient. 21. The method of claim 21, wherein the patient suffers from macular degeneration (AMD), ocular angiogenesis, retinal ganglion cell injury, or brain injury. 21. The method of claim 21, wherein the ocular angiogenesis comprises retinal angiogenesis. 21. The method of claim 21, wherein the ophthalmic composition is a topical eye drop. Claimed that the ophthalmic composition comprises an effective amount of a rifampicin compound selected from the group consisting of rifampicin, rifabutin, rifapentine, and rifaximin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Item 21. 25. The method of claim 25, wherein the pharmaceutically acceptable carrier comprises a tonicity regulator. 25. The method of claim 25, wherein the tonicity adjusting agent is saline solution, dextrose, glycerin, aqueous potassium chloride solution, buffer salt, propylene glycol, or mannitol.

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